Oleoylethanolamide Delays the Dysfunction and Death of Purkinje Cells and Ameliorates Behavioral Defects in a Mouse Model of Cerebellar Neurodegeneration
| Autor: | Eduardo Weruaga, David Díaz, Carlos del Pilar, Annie Andrieux, Rodrigo Muñoz-Castañeda, Carmelo Antonio Ávila-Zarza, Jose M. Muñoz-Castañeda, Ester Pérez-Martín, José R. Alonso, Marie-Jo Moutin |
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| Přispěvatelé: | Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Neurosciences of Castilla y León (INCYL) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Cerebellum Purkinje cell Mice Transgenic Oleic Acids Pharmacology Neuroprotection Mice Purkinje Cells 03 medical and health sciences Oleoylethanolamide chemistry.chemical_compound 0302 clinical medicine Cerebellar Diseases medicine Cerebellar Degeneration Animals Pharmacology (medical) Cells Cultured Neuroinflammation ComputingMilieux_MISCELLANEOUS Mice Knockout Cell Death business.industry Neurodegeneration Neurodegenerative Diseases medicine.disease Endocannabinoid system 3. Good health Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Mice Inbred DBA Original Article Neurology (clinical) business 030217 neurology & neurosurgery [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Endocannabinoids |
| Zdroj: | Neurotherapeutics Neurotherapeutics, Springer Verlag, 2021, ⟨10.1007/s13311-021-01044-3⟩ |
| ISSN: | 1933-7213 |
| Popis: | Oleoylethanolamide (OEA) is an endocannabinoid that has been proposed to prevent neuronal damage and neuroinflammation. In this study, we evaluated the effects of OEA on the disruption of both cerebellar structure and physiology and on the behavior of Purkinje cell degeneration (PCD) mutant mice. These mice exhibit cerebellar degeneration, displaying microtubule alterations that trigger the selective loss of Purkinje cells and consequent behavioral impairments. The effects of different doses (1, 5, and 10 mg/kg, i.p.) and administration schedules (chronic and acute) of OEA were assessed at the behavioral, histological, cellular, and molecular levels to determine the most effective OEA treatment regimen. Our in vivo results demonstrated that OEA treatment prior to the onset of the preneurodegenerative phase prevented morphological alterations in Purkinje neurons (the somata and dendritic arbors) and decreased Purkinje cell death. This effect followed an inverted U-shaped time-response curve, with acute administration on postnatal day 12 (10 mg/kg, i.p.) being the most effective treatment regimen tested. Indeed, PCD mice that received this specific OEA treatment regimen showed improvements in motor, cognitive and social functions, which were impaired in these mice. Moreover, these in vivo neuroprotective effects of OEA were mediated by the PPARα receptor, as pretreatment with the PPARα antagonist GW6471 (2.5 mg/kg, i.p.) abolished them. Finally, our in vitro results suggested that the molecular effect of OEA was related to microtubule stability and structure since OEA administration normalized some alterations in microtubule features in PCD-like cells. These findings provide strong evidence supporting the use of OEA as a pharmacological agent to limit severe cerebellar neurodegenerative processes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01044-3. |
| Databáze: | OpenAIRE |
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